This invention relates to novel indolizine compounds useful for inhibiting sPLA2 mediated release of fatty acids for conditions such as septic shock.
The structure and physical properties of human non-pancreatic secretory phospholipase A2 (hereinafter called, xe2x80x9csPLA2xe2x80x9d) has been thoroughly described in two articles, namely, xe2x80x9cCloning and Recombinant Expression of Phospholipase A2 Present in Rheumatoid Arthritic Synovial Fluidxe2x80x9d by Seilhamer, Jeffrey J.; Pruzanski, Waldemar; Vadas Peter; Plant, Shelley; Miller, Judy A.; Kloss, Jean; and Johnson, Lorin K.; The Journal of Biological Chemistry, Vol. 264, No. 10, Issue of April 5, pp. 5335-5338, 1989; and xe2x80x9cStructure and Properties of a Human Non-pancreatic Phospholipase A2xe2x80x9d by Kramer, Ruth M.; Hession, Catherine; Johansen, Berit; Hayes, Gretchen; McGray, Paula; Chow, E. Pingchang; Tizard, Richard; and Pepinsky, R. Blake; The Journal of Biological Chemistry, Vol. 264, No. 10, Issue of April 5, pp. 5768-5775, 1989; the disclosures of which are incorporated herein by reference.
It is believed that sPLA2 is a rate limiting enzyme in the arachidonic acid cascade which hydrolyzes membrane phospholipids. Thus, it is important to develop compounds which inhibit sPLA2 mediated release of fatty acids (e.g., arachidonic acid). Such compounds would be of value in general treatment of conditions induced and/or maintained by overproduction of sPLA2; such as septic shock, adult respiratory distress syndrome, pancreatitis, trauma, bronchial asthma, allergic rhinitis, rheumatoid arthritis, gout, glomerulonephritis, and etc.
U.S. Pat. No. 2,825,734 describes the preparation of 3-(2-amino-1-hydroxyethyl) indoles using 3-indole glyoxylamide intermediates such as 1-phenethyl-2-ethyl-6-carboxy-N-propyl-3-indoleglyoxylamide (see, Example 30).
U.S. Pat. No. 2,890,233 describes several amide derivatives of 3-indoleacetic acids.
U.S. Pat. Nos. 3,196,162; 3,242,162; 3,242,163; and 3,242,193 (see, Col. 3, lines 55-60, Example 56) describe indolyl aliphatic acids together with their related esters and amides.
U.S. Pat. No. 3,271,416 describes indolyl aliphatic acids as sun screening agents and intermediates. These acids may be xe2x80x94NH2 substituted.
U.S. Pat. No. 3,351,630 describes alpha-substituted 3-indolyl acetic acid compounds and their preparation inclusive of glyoxylamide intermediates.
U.S. Pat. No. 3,449,363 describes trifluoromethylindoles having glyoxylamide groups at the 3 position of the indole nucleus. These compounds are stated to be analgesics.
U.S. Pat. No. 5,132,319 describes certain 1-(hydroxylaminoalkyl)indoles derivatives as inhibitors of leukotriene biosynthesis.
The article, xe2x80x9cStructure-activity relationships leading to WAY-121,520, a tris aryl-type, indomethacin-based, phospholipase A2 (PLA2)/leukotriene biosynthesis inhibitorxe2x80x9d, by A Kreft, et. al., Agents and Actions, Special Conference Issue Vol. 39 (1993),pp. C33-C35, ISSN 0065-4299, published by Birkhauser Verlag, Basel Switzerland; (Proceedings of the Sixth International Conference of the Inflammation Research Association, Sep. 20-24, 1992, at White Haven, Pa./USA, Guest Editors, D. W. Morgan and A. K. Welton) describes the inhibition of phospholipase A2 by indomethacin analogs. Indole compounds having benzyl and acidic substituents are described.
The article, (Short communication) entitled, xe2x80x9cIndolizine derivatives with biological activity VI 1-(2-aminoethyl)-3-benzyl-7-methoxy-2-methylindolizine, benanserin structural analoguexe2x80x9d by G M Cingolani, F. Claudi, M. Massi, and F. Venturi, Eur. J. Med. Chem. (1990) 25, pp. 709-712 publ. by Elsevier, Paris describes selected indolizines and their activity on smooth muscle.
The article, xe2x80x9cIndolizine Analogues of Indomethacinxe2x80x9d by C. Casagrande, A. Invernizzi, R. Ferrini, and G. Miragoli, Il Farmacoxe2x80x94Ed. Sc.xe2x80x94Vol. 26xe2x80x94fasc. 12, pp. 1059-1073, describes pharmacological tests with selected indomethacin analogues.
European Patent Application No. 0 519 353 (Application No. 92109968.5) describes indolizin derivatives which have pharmacological activities such as inhibitory activity on testosteron reductase.
European Patent Application No. 0 620 214 (Application No. 94302646.8 describes hydrazide derivatives of indoles having sPLA2 inhibitory activity.
It is desirable to develop new compounds and treatments for sPLA2 induced diseases.
This invention is a novel use of indolizine compounds having the nucleus and substituent numbering positions shown in the following formula: 
Moreover, this invention is a class of novel indolizine compounds having two general configurations shown in structural formulae xe2x80x9cAxe2x80x9d and xe2x80x9cBxe2x80x9d below: 
In configuration xe2x80x9cAxe2x80x9d an acetamide, acetic acid hydrazide or glyoxylamide moiety is present at the 1 position, a large (C7-C30) organic (e.g., carbocyclic) group is present at the 3 position and an acidic group is at the 7 or 8 positions. 
In configuration xe2x80x9cBxe2x80x9d an acetamide, acetic aced hydrazide or glyoxylamide moiety is present at the 3 position, a large (C7-C30) organic (e.g., carbocyclic) group is present at the 1 position and an acidic group is at the 5 or 6 positions.
These indolizine-1-functional and indolizine-3-functional compounds of the invention are effective in inhibiting human sPLA2 mediated release of fatty acids.
This invention is also a pharmaceutical composition containing indolizine-1-functional or indolizine-3-functional compounds selected from the group consisting of the novel indolizine compounds represented by the general formulae xe2x80x9cAxe2x80x9d and xe2x80x9cBxe2x80x9d and mixtures thereof.
This invention is also a method of preventing and treating septic shock, adult respiratory distress syndrome, pancreatitis, trauma, bronchial asthma, allergic rhinitis, rheumatoid arthritis, gout, glomerulonephritis, and related diseases by contact with a therapeutically effective amount of indolizine-1-functional and indolizine-3-functional compounds selected from the group consisting of the novel indolizine compounds represented by the general formulae xe2x80x9cAxe2x80x9d or xe2x80x9cBxe2x80x9d and mixtures thereof.
The indolizine acetamides, acetic acid hydrazides (hereinafter called, xe2x80x9chydrazidesxe2x80x9d), and glyoxylamides of the invention employ certain defining terms as follows:
The term, xe2x80x9calkylxe2x80x9d by itself or as part of another substituent means, unless otherwise defined, a straight or branched chain monovalent hydrocarbon radical such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tertiary butyl, isobutyl, sec-butyl, n-pentyl, and n-hexyl.
The term, xe2x80x9calkenylxe2x80x9d employed alone or in combination with other terms means a straight chain or branched monovalent hydrocarbon group having the stated number ange of carbon atoms, and typified by groups such as vinyl, propenyl, crotonyl, isopentenyl, and various butenyl isomers.
The term, xe2x80x9chydrocarbylxe2x80x9d means an organic group containing only carbon and hydrogen.
The term, xe2x80x9ccarbocyclic radicalxe2x80x9d refers to radicals derived from a saturated or unsaturated, substituted or unsubstituted 5 to 14 membered organic nucleus whose ring forming atoms (other than hydrogen) are solely carbon atoms.
The term, xe2x80x9chaloxe2x80x9d means fluoro, chloro, bromo, or iodo.
The term, xe2x80x9cheterocyclic radicalxe2x80x9d, refers to radicals derived from monocyclic or polycyclic, saturated or unsaturated, substituted or unsubstituted heterocyclic nuclei having 5 to 14 ring atoms and containing from 1 to 3 hetero atoms selected from the group consisting of nitrogen, oxygen or sulfur. Typical heterocyclic radicals are pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, phenylimidazolyl, triazolyl, isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl, indolyl, carbazolyl, norharmanyl, azaindolyl, benzofuranyl, dibenzofuranyl, thianaphtheneyl, dibenzothiophenyl, indazolyl, imidazo(1.2-A)pyridinyl, benzotriazolyl, anthranilyl, 1,2-benzisoxazolyl, benzoxazolyl, benzothiazolyl, purinyl, pyridinyl, dipyridinyl, phenylpyridinyl, benzylpyridinyl, pyrimidinyl, phenylpyrimidinyl, pyrazinyl, 1,3,5-triazinyl, quinolinyl, phthalazinyl, quinazolinyl, and quinoxalinyl.
Typical carbocyclic radicals are cycloalkyl, cycloalkenyl, phenyl, naphthyl, norbornanyl, bicycloheptadienyl, toluyl, xylenyl, indenyli stilbenyl, terphenylyl, diphenylethylenyl, phenyl-cyclohexenyl, acenaphthylenyl, and anthracenyl, biphenyl, bibenzylyl and related bibenzylyl homologues represented by the formula (bb), 
where n is a number from 1 to 8.
The term, xe2x80x9cnon-interfering substituentxe2x80x9d, refers to radicals which do not prevent or significantly reduce the inhibition of sPLA2 mediated release of fatty acids. Non-interfering substituents are suitable for substitution at positions 5, 6, 7 and/or 8 on the indolizine nucleus (as hereinafter depicted in Formula IA) and for radical(s) suitable for substitution on the heterocyclic radical and carbocyclic radical as defined above. Illustrative non-interfering radicals are C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C7-C12 aralkyl, C7-C12 alkaryl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, phenyl, toluyl, xylenyl, biphenyl, C1-C6 alkoxy, C1-C6 alkenyloxy, C1-C6 alkynyloxy, C2-C12 alkoxyalkyl, C2-C12 alkoxyalkyloxy, C2-C12 alkylcarbonyl, C2-C12 alkylcarbonylamino, C2-C12 alkoxyamino, C2-C12 alkoxyaminocarbonyl, C1-C12 alkylamino, C1-C6 alkylthio, C2-C12 alkylthiocarbonyl, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 haloalkoxy, C1-C6 haloalkylsulfonyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, xe2x80x94C(O)O(C1-C6 alkyl), xe2x80x94(CH2)nxe2x80x94Oxe2x80x94(C1-C6 alkyl), benzyloxy, phenoxy, phenylthio, xe2x80x94(CONHSO2R), xe2x80x94CHO, amino, amidino, bromo, carbamyl, carboxyl, carbalkoxy, xe2x80x94(CH2)nxe2x80x94CO2H, chloro, cyano, cyanoguanidinyl, fluoro, guanidino, hydrazide, hydrazino, hydrazido, hydroxy, hydroxyamino, iodo, nitro, phosphono, xe2x80x94SO3H, thioacetal, thiocarbonyl, and C1-C6 carbonyl; where n is from 1 to 8.
The term, xe2x80x9cacidic groupxe2x80x9d means an organic group which when attached to an indolizine nucleus, through suitable linking atoms (hereinafter defined as the xe2x80x9cacid linkerxe2x80x9d), acts as a proton donor capable of hydrogen bonding. Illustrative of an acidic group are the following: 
where n is 1 to 8, R89 is a metal or C1-C10 alkyl, and R99 is hydrogen or C1-C10 alkyl.
The words, xe2x80x9cacid linkerxe2x80x9d refer to a divalent linking group symbolized as, xe2x80x94(La)xe2x80x94, which has the function of joining the indolizine nucleus to an acidic group in the general relationship: 
The words, xe2x80x9cacid linker lengthxe2x80x9d, refer to the number of atoms (excluding hydrogen) in the shortest chain of the linking group xe2x80x94(La)xe2x80x94 that connects the indolizine nucleus with the acidic group. The presence of a carbocyclic ring in xe2x80x94(La)xe2x80x94 counts as the number of atoms approximately equivalent to the calculated diameter of the carbocyclic ring. Thus, a benzene or cyclohexane ring in the acid linker counts as 2 atoms in calculating the length of xe2x80x94(La)xe2x80x94. Illustrative acid linker groups are; 
wherein, groups (a), (b), and (c) have acid linker lengths of 5, 7, and 2, respectively.
The term, xe2x80x9caminexe2x80x9d, includes primary, secondary and tertiary amines.
Type xe2x80x9cAxe2x80x9d Configuration Indolizine Comoounds of the Invention:
There are three types of Conf iguration type xe2x80x9cAxe2x80x9d indolizine compounds of the invention as represented by structural formulae (IA), (IIA), and (IIIA) below:
The indolizine-1-acetamides are represented by the formula (IA), below: 
where X is oxygen or sulfur and each R11 is independently hydrogen, C1-C3 alkyl, or halo and all other groups are as hereinafter defined.
The indolizine-1-hydrazides are represented by the formula (IIA), as set out below: 
where X is oxygen or sulfur and each R11 is independently hydrogen, C1-C3 alkyl, or halo and all other groups are as hereinafter defined.
The indolizine-1-glyoxylamides are represented by the formula (IIIA), as set out below: 
where X is independently oxygen or sulfur and all other groups are as hereinafter defined.
For formulae (IA), (IIA), and (IIIA) above the remaining groups are defined as follows:
R13 is selected from groups (a), (b) and (c) where;
(a) is C7-C20 alkyl, C7-C20 alkenyl, C7-C20 alkynyl, carbocyclic radical, or heterocyclic radical, or
(b) is a member of (a) substituted with one or more independently selected non-interfering substituents; or
(c) is the group xe2x80x94(L)xe2x80x94R80; where, xe2x80x94(L)xe2x80x94 is a divalent linking group of 1 to 12 atoms and where R80 is a group selected from (a) or (b);
R12 is hydrogen, halo, C1-C3 alkyl, C3-C4 cycloalkyl, C3-C4 cycloalkenyl, xe2x80x94Oxe2x80x94(C1-C2 alkyl), xe2x80x94Sxe2x80x94(C1-C2 alkyl), or a non-interfering substituent having a total of 1 to 3 atoms other than hydrogen; (that is, the R12 radical may contain hydrogen atoms, but the remaining atoms comprising the total of 1 to 3 are non-hydrogen);
R17 and R18 are independently selected from hydrogen, a non-interfering substituent, or the group, xe2x80x94(La)xe2x80x94(acidic group); wherein xe2x80x94(La)xe2x80x94, is an acid linker having an acid linker length of 1 to 10; provided, that at least one of R17 and R18 must be the combined group, xe2x80x94(La)xe2x80x94(acidic group); and
R15 and R16 are each independently selected from hydrogen, non-interfering substituent, carbocyclic radical, carbocyclic radical substituted with non-interfering substituents, heterocyclic radical, and heterocyclic radical substituted with non-interfering substituents.
Preferred Subarouis of Type xe2x80x9cAxe2x80x9d Indolizine Compounds of the Invention:
A preferred subclass of compounds of formulae (IA), (IIA), and (IIIA) are those wherein all X are oxygen.
Another preferred subclass of compounds of formulae (IA), (IIA), and (IIIA) are those wherein R12 is selected from the group; halo, cyclopropyl, methyl, ethyl, propyl, xe2x80x94O-methyl, and xe2x80x94S-methyl.
Another preferred subclass of compounds of formulae (IA), (IIA) and (IIIA) are those wherein for R13, xe2x80x94(L)xe2x80x94 is selected from the group consisting of: 
Another preferred subclass of compounds of formulae (IA), (IIA), and (IIIA) are those wherein for R13, group R80 is carbocyclic and is selected from the group consisting of cycloalkyl, cycloalkenyl, phenyl, naphthyl, norbornanyl, bicycloheptadienyl, toluyl, xylenyl, indenyl, stilbenyl, terphenylyl, diphenylethylenyl, phenyl-cyclohexenyl, acenaphthylenyl, and anthracenyl, biphenyl, bibenzylyl and related bibenzylyl homologues represented by the formula (bb), 
where n is a number from 1 to 8. Particularly preferred are compounds wherein R13 is selected from the group consisting of 
where R10 is a radical independently selected from halo, C1-C10 alkyl, C1-C10 alkoxy, xe2x80x94Sxe2x80x94(C1-C10 alkyl), and C1-C10 haloalkyl, q is a number from 0 to 4, and t is a number from 0 to 5.
Another preferred subclass of compounds of formulae (IA), (IIA), and (IIIA) are those wherein R18 is a substituent having an acid linker with an acid linker length of 2 or 3.
Another preferred subclass of compounds of formulae (IA), (IIA), and (IIIA) are those wherein R18 comprises an acidic group and the acid linker for the acidic group has an acid linker length of 2 or 3 and the acid linker group, xe2x80x94(La)xe2x80x94, for R18 is selected from the group represented by the formula; 
where Q is selected from the group xe2x80x94(CH2)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, and xe2x80x94Sxe2x80x94, and R84 and R85 are each independently selected from hydrogen, C1-C10 alkyl, aryl, C1-C10 alkaryl, C1-C10 aralkyl, carboxy, carbalkoxy, and halo. Most preferred are compounds where the acid linker, xe2x80x94(La)xe2x80x94, for R18 is selected from the specific groups; 
where R is H or C1-C4 alkyl.
Another preferred subclass of compounds of formulae (IA), (IIA), and (IIIA) are those wherein R17 comprises an acidic group and the acid linker of the R17 acidic group has an acid linker with an acid linker length of 3 to 10 atoms and the acid linker group, xe2x80x94(La)xe2x80x94, for R17 is selected from; 
where r is a number from 1 to 7, s is 0 or 1, and Q is selected from the group xe2x80x94(CH2)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, and xe2x80x94Sxe2x80x94, and R84 and R85 are each independently selected from hydrogen, C1-C10 alkyl, aryl, C1-C10 alkaryl, C1-C10 aralkyl, carboxy, carbalkoxy, and halo. Most preferred are compounds where the acid linker, xe2x80x94(La)xe2x80x94, for R17 is selected from the specific groups: 
wherein; R is hydrogen or C1-C4 alkyl, R84 and R85 are each independently selected from hydrogen, C1-C10 alkyl, aryl, C1-C10 alkaryl, C1-C10 aralkyl, carboxy, carbalkoxy, and halo.
Another preferred subclass of compounds of formulae (IA), (IIA), (IIIA) are those wherein the acidic group (or salt, and prodrug derivatives thereof) on R17 and/or R18 is selected from the following: 
where n is 1 to 8, R89 is a metal or C1-C10 alkyl, and R99 is hydrogen or C1-C10 alkyl. Particularly preferred are compounds wherein the acidic group of R17 and R18 is selected from; 
or salt, and prodrug (e.g., ester) derivatives thereof. The carboxyl group is the most preferred acidic group. It is highly preferred that only one of R17 or R18 contain an acidic group.
Another preferred subclass of compounds of formula (IA), (IIA), and (IIIA) are those wherein R15 and R16 are each independently selected from hydrogen and non-interfering substituents, with the non-interfering substituents being selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C7-C12 aralkyl, C7-C12 alkaryl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, phenyl, toluyl, xylenyl, biphenyl, C1-C6 alkoxy, C1-C6 alkenyloxy, C1-C6 alkynyloxy, C2-C12 alkoxyalkyl, C2-C12 alkoxyalkyloxy, C2-C12 alkylcarbonyl, C2-C12 alkylcarbonylamino, C2-C12 alkoxyamino, C2-C12 alkoxyaminocarbonyl, C1-C12 alkylamino, C1-C6 alkylthio, C2-C12 alkylthiocarbonyl, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 haloalkoxy, C1-C6 haloalkylsulfonyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, xe2x80x94C(O)O(C1-C6 alkyl), xe2x80x94(CH2)nxe2x80x94Oxe2x80x94(C1-C6 alkyl), benzyloxy, phenoxy, phenylthio, xe2x80x94(CONHSO2R), xe2x80x94CHO, amino, amidino, bromo, carbamyl, carboxyl, carbalkoxy, xe2x80x94(CH2)nxe2x80x94CO2H, chloro, cyano, cyanoguanidinyl, fluoro, guanidino, hydrazide, hydrazino, hydrazido, hydroxy, hydroxyamino, iodo, nitro, phosphono, xe2x80x94SO3H, thioacetal, thiocarbonyl, and C1-C6 carbonyl; where n is from 1 to 8.
B) Type xe2x80x9cBxe2x80x9d Indolizine-3-acetamide Compounds of the Invention Having the General Formula (IB):
A) The Indolizine-3-acetamides are Represented by the Formula (IB), below: 
where each R3 is independently hydrogen, C1-C3 alkyl, or halo; X is selected from oxygen or sulfur; and all other groups are as hereinafter defined.
B) The Indolizine-3-hydrazides are Represented by the Formula (IIB), below: 
each R3 is independently, hydrogen, C1-C3 alkyl, or halo; X is selected from oxygen or sulfur; and all other groups are as hereinafter defined.
C) The Indolizine-1-glyoxylamides are Represented by the Formula (IIIB), below: 
where each X is independently selected from oxygen and sulfur, and all other groups are as hereinafter defined.
For formulae (IB), (IIB), and (IIIB) above the remaining groups are defined as follows:
R1 is selected from groups (a), (b) and (c) where;
(a) is C7-C20 alkyl, C7-C20 alkenyl, C7-C20 alkynyl, carbocyclic radicals, or heterocyclic radicals, or
(b) is a member of (a) substituted with one or more independently selected non-interfering substituents; or
(c) is the group xe2x80x94(L)xe2x80x94R80; where, xe2x80x94(L)xe2x80x94 is a divalent linking group of 1 to 12 atoms and where R80 is a group selected from (a) or (b);
R2 is hydrogen, halo, C1-C3 alkyl, C3-C4 cycloalkyl, C3-C4 cycloalkenyl, xe2x80x94Oxe2x80x94(C1-C2 alkyl), xe2x80x94Sxe2x80x94(C1-C2 alkyl), or a non-interfering substituent having a total of 1 to 3 atoms other than hydrogen; (that is, the R2 radical may contain hydrogen atoms, but the remaining atoms comprising the total of 1 to 3 are non-hydrogen);
R5 and R6 are independently selected from hydrogen, a non-interfering substituent, or the group, xe2x80x94(La)xe2x80x94(acidic group); wherein xe2x80x94(La)xe2x80x94, is an acid linker having an acid linker length of 1 to 10; provided, that at least one of R5 and R6 must be the group, xe2x80x94(La)xe2x80x94(acidic group);
R7 and R8 are each independently selected from hydrogen, non-interfering substituent, carbocyclic radicals, carbocyclic radicals substituted with non-interfering substituents, heterocyclic radicals, and heterocyclic radicals substituted with non-interfering substituents.
Preferred Subgroups of Type xe2x80x9cBxe2x80x9d Indolizine Compunds of the Invention:
A preferred subclass of compounds of formulae (IB), (IIB), and (IIIB) are those wherein all X are oxygen.
Another preferred subclass of compounds of formulae (IB), (IIB), and (IIIB) are those wherein R2 is selected from the group; halo, cyclopropyl, methyl, ethyl, propyl, xe2x80x94O-methyl, and xe2x80x94S-methyl.
Another preferred subclass of compounds of formulae (IB), (IIB) and (IIIB) are those wherein for R1 xe2x80x94(L)xe2x80x94 is selected from the group consisting of: 
Another preferred subclass of compounds of formulae (IB), (IIB), and (IIIB) are those wherein for R1, group R80 is carbocyclic and is selected from the group consisting of cycloalkyl, cycloalkenyl, phenyl, naphthyl, norbornanyl, bicycloheptadienyl, toluyl, xylenyl, indenyl, stilbenyl, terphenylyl, diphenylethylenyl, phenyl-cyclohexenyl, acenaphthylenyl, and anthracenyl, biphenyl, bibenzylyl and related bibenzylyl homologues represented by the formula (bb), 
where n is a number from 1 to 8. Particularly preferred are compounds wherein R1 is selected from the group consisting of 
where R10 is a radical independently selected from halo, C1-C10 alkyl, C1-C10 alkoxy, xe2x80x94Sxe2x80x94(C1-C10 alkyl), and C1-C10 haloalkyl, q is a number from 0 to 4, and t is a number from 0 to 5.
Another preferred subclass of compounds of formulae (IB), (IIB), and (IIIB) are those wherein R5 is a substituent having an acid linker with an acid linker length of 2 or 3.
Another preferred subclass of compounds of formulae (IB), (IIB), and (IIIB) are those wherein R5 comprises an acidic groupand the acid linker for the acidic group has an acid linker length of 2 or 3 and the acid linker group, xe2x80x94(La)xe2x80x94, for R5 is selected from the group represented by the formula; 
where Q is selected from the group xe2x80x94(CH2)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, and xe2x80x94Sxe2x80x94, and R84 and R85 are each independently selected from hydrogen, C1-C10 alkyl, aryl, C1-C10 alkaryl, C1-C10 aralkyl, carboxy, carbalkoxy, and halo. Most preferred are compounds where the acid linker, xe2x80x94(La)xe2x80x94, for R5 is selected from the specific groups; 
where R is H or C1-C4 alkyl.
Another preferred subclass of compounds of formulae (IB), (IIB), and (IIIB) are those wherein R6 comprises an acidic group and the acid linker of the R6 acidic group has an acid linker with an acid linker length of 3 to 10 atoms and the acid linker group, xe2x80x94(La)xe2x80x94, for R6 is selected from; 
where r is a number from 1 to 7, s is 0 or 1, and Q is selected from the group xe2x80x94(CH2)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, and xe2x80x94Sxe2x80x94, and R84 and R85 are each independently selected from hydrogen, C1-C10 alkyl, aryl, C1-C10 alkaryl, C1-C10 aralkyl, carboxy, carbalkoxy, and halo. Most preferred are compounds where the acid linker, xe2x80x94(La)xe2x80x94, for R6 is selected from the specific groups; 
wherein; R is hydrogen or C1-C4 alkyl, R84 and R85 are each independently selected from hydrogen, C1-C10 alkyl, aryl, C1-C10 alkaryl, C1-C10 aralkyl, carboxy, carbalkoxy, and halo.
Another preferred subclass of compounds of formulae (IB), (IIB), (IIIB) are those wherein the acidic group (or salt, and prodrug derivatives thereof) on R5 and/or R6 is selected from the following: 
where n is 1 to 8, R89 is a metal or C1-C10 alkyl, and R99 is hydrogen or C1-C10 alkyl. Particularly preferred are compounds wherein the acidic group of R5 and/or R6 is selected from; 
or salt, and prodrug (e.g., ester) derivatives thereof. The carboxyl group is the most preferred of all acidic groups. It is also highly preferred that only one of R5 or R6 contain an acidic group.
Another preferred subclass of compounds of formulae (IB), (IIB) and (IIIB) are those wherein R7 and R8 are each independently selected from hydrogen and non-interfering substituents, with the non-interfering substituents being selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C7-C12 aralkyl, C7-C12 alkaryl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, phenyl, toluyl, xylenyl, biphenyl, C1-C6 alkoxy, C1-C6 alkenyloxy, C1-C6 alkynyloxy, C2-C12 alkoxyalkyl, C2-C12 alkoxyalkyloxy, C2-C12 alkylcarbonyl, C2-C12 alkylcarbonylamino, C2-C12 alkoxyamino, C2-C12 alkoxyaminocarbonyl, C1-C12 alkylamino, C1-C6 alkylthio, C2-C12 alkylthiocarbonyl, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 haloalkoxy, C1-C6 haloalkylsulfonyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, xe2x80x94C(O)O(C1-C6 alkyl), xe2x80x94(CH2)nxe2x80x94Oxe2x80x94(C1-C6 alkyl), benzyloxy, phenoxy, phenylthio, xe2x80x94(CONHSO2R), xe2x80x94CHO, amino, amidino, bromo, carbamyl, carboxyl, carbalkoxy, xe2x80x94(CH2)nxe2x80x94CO2H, chloro, cyano, cyanoguanidinyl, fluoro, guanidino, hydrazide, hydrazino, hydrazido, hydroxy, hydroxyamino, iodo, nitro, phosphono, xe2x80x94SO3H, thioacetal, thiocarbonyl, and C1-C6 carbonyl; where n is from 1 to 8.
Specific preferred compounds (inclusive of all pharmaceutically acceptable salts, solvates and prodrug derivatives thereof) of the invention are represented by formulae shown in Sections (AA), (AB), and (AC) below:
(AA) Indolizine Compounds of Type xe2x80x9cAxe2x80x9d Having Acetamide Functionality 
and mixtures of the above compounds.
(AB) Indolizine Compounds of Type xe2x80x9cAxe2x80x9dxe2x80x94With Glyoxylamide Functionality 
and mixtures of the above compounds.
(AC) Indolizine Comoounds of Type xe2x80x9cBxe2x80x9dxe2x80x94With Glyoxylamide Functionality
An indolizine-3-acetamide functional compound and a pharmaceutically acceptable salt, solvate or prodrug derivative thereof; wherein said compound is selected from the group represented by the following formulae: 
and mixtures of the above compounds.
The salts of the above indolizine-1-funcrional and indolizine-3-functional compounds represented by formulae (IA), (IIA), (IIIA), (IB), (IIB), (IIIB) and the individual formulae of Sections (AA), (AB) and (AC), supra, are an additional aspect of the invention. In those instances where the compounds of the invention possess acidic or basic functional groups various salts may be ormed which are more water soluble and physiologically suitable than the parent compound. Representative pharmaceutically acceptable salts, include but are not limited to, the alkali and alkaline earth salts such as lithium, sodium, potassium, calcium, magnesium, aluminum and the like. Salts are conveniently prepared from the free acid by treating the acid in solution with a base or by exposing the acid to an ion exchange resin.
Included within the definition of pharmaceutically acceptable salts are the relatively non-toxic, inorganic and organic base addition salts of compounds of the present invention, for example, ammonium, quaternary ammonium, and amine cations, derived from nitrogenous bases of sufficient basicity to form salts with the compounds of this invention (see, for example, S. M. Berge, et al., xe2x80x9cPharmaceutical Salts,xe2x80x9d J. Phar. Sci., 66: pp.1-19 (1977)). Moreover, the basic group(s) of the compounds of the invention may be reacted with suitable organic or inorganic acids to form salts such as acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, camsylate, carbonate, chloride, clavulanate, citrate, chloride, edetate, edisylate, estolate, esylate, fluoride, fumarate, gluceptate, gluconate, glutamate, glycolylarsanilate, hexylresorcinate, bromide, chloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, malseate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, oleate, oxalate, palmitate, pantothenate, phosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, tannate, tartrate, tosylate, trifluoroacetate, trifluoromethane sulfonate, and valerate.
Certain compounds of the invention may possess one or more chiral centers and may thus exist in optically active forms. Likewise, when the compounds contain an alkenyl or alkenylene group there exists the possibility of cis- and trans- isomeric forms of the compounds. The R- and S- isomers and mixtures thereof, including racemic mixtures as well as mixtures of cis- and trans-isomers, are contemplated by this invention. Additional asymmetric carbon atoms can be present in a substituent group such as an alkyl group. All such isomers as well as the mixtures thereof are intended to be included in the invention. If a particular stereoisomer is desired, it can be prepared by methods well known in the art by using stereospecific reactions with starting materials which contain the asymmetric centers and are already resolved or, alternatively by methods which lead to mixtures of the stereoisomers and subsequent resolution by known methods.
Prodrugs are derivatives of the compounds of the invention which have chemically or metabolically cleavable groups and become by solvolysis or under physiological conditions the compounds of the invention which are pharmaceutically active in vivo. The prodrug derivative form often offers advantages of solubility, tissue compatibility, or delayed release in a mammalian organism (see, Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acidic compound with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a suitable amine. Simple aliphatic or aromatic esters derived from acidic groups pendent on the compounds of this invention are preferred prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy) alkyl esters or ((alkoxycarbonyl)oxy)alkyl esters.
The following abbreviations are used throughout the synthesis Schemes and Examples:

The anion of 2-methyl-5-methoxypyridine is formed in THF using lithium diisopropyl amide and reacted with benzonitrile to produce 2. Alkylation of the nitrogen of 2 by 1-bromo-2-butanone followed by base catalyzed cyclization forms 3 which is reduced by LAH to 4. Sequential treatment of 4 with oxalyl chloride and ammonia gives 8. Alternatively, 4 is acylated with ethyl oxalyl chloride to give 5 which is converted to 6 with lithium hydroxide and then to 8 by sequential treatment with ethyl chloroformate and ammonium hydroxide. Demethylation of 8 by BBr3 yields 9 which is O-alkylated using base and ethyl 4-bromobutyrate to form 10. Hydrolysis of 10 by aqueous base produces 11. 
Compound 12 (N. Desidiri, A. Galli, I. Sestili, and M. L. Stein, Arch. Pharm. (Weinheim) 325, 29, (1992)) is reduced by hydrogen in the presence of Pd/C to 14 which gives 15 on ammonolysis using ammonium hydroxide. O-alkylation of 15 using benzyl chloride and base affords 16. Alkylation of the nitrogen atom of 13 or 16 by 1-bromo-2-ketones followed by base catalyzed cyclization yields indolizines 17 which are acylated by aroyl halides to form 18. 
Reduction of 18 by tert-butylamine-borohydride and aluminum chloride yields 19 which is reduced by hydrogen in the presence of Pd/C to give 20. O-alkylation of 20 by benzyl bromoacetate and base forms 21 which is converted to the acid 22 by debenzylation using hydrogen in the presence of Pd/C. 
Compound 23 (N. Desideri F. Manna, M. L. Stein, G. Bile, W. Filippeelli, and E. Marmo, Eur. J. Med. Chem. Chim. Ther., 18, 295, (1983)) is O-alkylated using sodium hydride and benzyl chloride to give 24. N-alkylation of 24 by 1-bromo-2-butanone or chloromethylcyclopropyl ketone and subsequent base catalyzed cyclization gives 25 which is acylated by aroyl halide to give 26. Hydrolysis of the ester function of 26 followed by acidification forms an acid which is thermally decarboxylated to give 27. Reduction of the ketone function of 27 by LAH yields indolizines 28. 
Heating a mixture of 3-bromo-4-phenyl-butan-2-one or 3-bromo-4-cyclohexyl-butan-2-one and ethyl pyridine-2-acetate, or a substituted derivative, in the presence of base yields indolizine 31. Treatment of 31 with aqueous base in DMSO at elevated temperature followed by acidification gives 32 which is thermally decarboxylated to 33. 
Sequential treatment of 28 or 33 with oxalyl chloride and ammonium hydroxide forms 35 which is debenzylated by hydrogen in the presence of Pd/C to give 36. Indolizines 36 are O-alkylated using sodium hydride and bromoacetic acid esters to form 37, 38, or 39 which are converted to indolizines 40 by hydrolysis with aqueous base followed by acidification. 
The O-alkylation of 36 h produces nitrite 41 which is converted to 42 on reaction with trialkyltin azide. 
The hydroxypyridine is O-alkylated to give 44 which is heated with 2-haloketones to produce 45. Treatment of 45 with base causes cyclization to 46 which on heating with acid chlorides yields acylindolizines 47 which are reduced by aluminum hydride to the corresponding alkylindolizines 48. Sequential treatment of 48 with oxalyl chloride and then ammonia gives 49. Cleavage of the ether functionality of 49 yields 50. The oxyacetic ester derivatives 51 are formed by O-alkylation of 50 and then hydrolyzed to the oxyacetic acids 52. 
Pyridine 43 is O-alkylated to produce 53. Heating 53 with 2-haloketones gives intermediate N-alkylated pyridinium compounds which are cyclized to 54 on treatment with base. Heating 54 with acyl chlorides gives the acylindolizines 55 which are reduced to the alkylindolizines 56 by sodium borohydride-aluminum chloride. Alternatively, 56 are produced by C-alkylation of 54 using alkyl halides. Sequential treatment of 56 with oxalyl chloride and then ammonia gives 57 which are hydrolyzed to produce 58. Compound 58b is converted to its sodium salt 59a which yields 59b-k on reaction with the appropriate alkyl halide. 
Compound 36b is O-alkylated to give 591-p. 
Pyridine 60 is N-alkylated by 2-haloketones to produce intermediate pyridinium compounds which are cyclized by base to give 61. Reaction of 61 with acyl chlorides produces 62 which are reduced to 63 by tert butylamine-borane and aluminum chloride. Sequential treatment of 63 with oxalyl chloride and then ammonia yields 64 which are O-demethylated by BBr3 to give 65. The sodium salt of 65 is reacted with ethyl 4-bromobutyrate to give 66 which is hydrolyzed to the acid 67. 
Compounds 36d and 65c are O-alkylated by omega-bromnocarboxylic esters to give 68 which are hydrolyzed to the acids 69. Compounds 36d and 65c produce 70 on treatment with propiolactone and base. 
Compounds 66 are reduced to 71 by tert-butylamine-borane and aluminum chloride. 
Pyridine 44b reacts with ethyl bromoacetate to produce 72 which is treated with CS2 and base and then with ethyl acrylate to form 73. Reaction of 73 with base and ethyl bromoacetate yields a mixture of regioisomers 74a+b, 6- and 8-benzyloxy compounds. Base treatment of 74a+b eliminates ethyl acrylate to form 75 which is separated from the isomer of 6-benzyloxy derivative and S-alkylated to give 76. Hydrolysis of 76 forms 77 which is thermally decarboxylated to yield 78. Compound 78 is C-alkylated to form 79 which on sequential treatment with oxalyl chloride and then ammonia forms 80. Ether cleavage of 80 gives 81 whose sodium salt is alkylated by methyl bromoacetate to form 82 which are hydrolyzed to acids 83. 
Aminopicoline 84 is converted to its N-CBZ derivative 85 whose anion is alkylated by methyl bromoacetate to produce 86. Reaction of 86 with methyl alpha-bromoalkyl ketones in the presence of base yields 87. Sequential treatment of 87 with oxalyl chloride and then ammonia gives 88 which is converted to 89 by hydrogenolysis of the N-CBZ function. Hydrolysis of 89 yields acids 90. 
Compounds 88 are reduced by tert-butylamine-borane and aliuminum chloride to 91 which are hydrolyzed to acids 92. 
Pyridine 24 is N-alkylated by methyl bromoacetate, cyclized with base, and o-methylated using dimethysulfate to give 94. Hydrolysis of the ester function of 94 followed by thermal decarboxylation yields 2-methoxy-8-benzyloxyindolizine which is C-alkylated at position 3 and then reacted sequentially with oxalyl chloride and ammonia to produce 95. Hydrogenolysis of the 8-benzyloxy group followed by O-alkylation gives 96 which is hydrolyzed to 97.